Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Swayback disease, a neurodegenerative disorder of lambs, and Menkes disease, the human equivalent, are caused by a deficiency of dietary copper. Reports of low enzymic activity suggest that several copper-containing enzymes, including cytochrome-c oxidase (COX), may influence the progress of these diseases. To investigate its role in the development of neurodegenerative disorders, in particular swayback disease, we isolated COX from the brains and livers of swayback-diseased lambs. Comparative sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) combined with densitometric analysis revealed that whereas the structure of COX from the liver of diseased animals was normal, the corresponding brain enzyme was subunits II-, III-, and IV-deficient; the deficiency was 55, 30, and 65% respectively. The activities of liver and brain COX from normal and diseased lambs were compared by polarographic assay at low ionic strength. Whereas the enzyme from normal brains and both forms of the liver enzyme yielded characteristic biphasic Eadie-Hofstee plots, the brain enzyme from diseased animals displayed a single phase with a K(m) of 4.7 +/- 2.4 x 10(-6) M: the K(m) values of COX from the normal brain were 12 +/- 2.5 x 10(-6) and 5.5 +/- 0.5 x 10(-7) M. We conclude that the altered enzyme structure accounts for the uncharacteristic kinetics and low activity we have observed for the isolated brain enzyme. We also conclude that the altered enzyme structure partly accounts for the low oxidase activity and decreased ATP synthesis that has been widely reported for brain tissue from swayback-diseased animals. We postulate that the subunit deficiency probably results from incomplete crosslinking between the subunits and the membrane, and predict that similar structural and kinetic factors may also account for low COX activity in Menkes disease.
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PMID:Cytochrome-c oxidase isolated from the brain of swayback-diseased sheep displays unusual structure and uncharacteristic kinetics. 1032 20

The trace metal copper is an essential cofactor for a number of biological processes, including mitochondrial oxidative phosphorylation, free-radical eradication, neurotransmitter synthesis and maturation, and iron metabolism. Consequently, copper transport at the cell surface and the delivery of copper to intracellular proteins are critical events in normal cellular homeostasis. Four genes have been reported to influence the cellular uptake and the delivery of copper to specific cell compartments and proteins. These include hCTR1, which regulates cellular copper uptake; HAH1, which mediates the transfer of copper to the Menkes and Wilson disease transporters; CCS, which is related to the transfer of copper to superoxide dismutase; and hCOX17, which directs trafficking of copper to mitochondrial cytochrome-c oxidase. At present, no genetic disorders have been associated with defects in these four copper transporter genes. In this study, we test the possibility that defective copper uptake or intracellular translocation represents the basic defect in three categories of candidate phenotypes among 22 patients: ethylmalonic encephalopathy; mitochondriopathies of unknown aetiology; and neurodevelopmental abnormalities with clinical and chemical evidence of copper deficiency. Mutation analyses of the copper uptake protein, hCTR1, and the three copper chaperones were performed by direct sequencing of the whole coding regions. No causative mutations were identified for the four copper transporter genes in 22 patients. A heterozygous polymorphism (847G>A) for CCS was detected in 7 patients. For the distinct disease entity ethylmalonic encephalopathy, we additionally show normal mRNA levels for each of the four genes. The negative results notwithstanding, we encourage ongoing study of additional patients with candidate phenotypes. Further, our results are consistent with the notion that other unknown copper-related transporters could be involved in diseases.
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PMID:Mutation analysis of copper transporter genes in patients with ethylmalonic encephalopathy, mitochondriopathies and copper deficiency phenotypes. 1287 41

Deficiencies of different proteins involved in copper metabolism have been reported to cause human diseases. Well-known syndromes, for example, are Menkes and Wilson diseases. Here we report a patient presenting with congenital cataract, severe muscular hypotonia, developmental delay, sensorineural hearing loss and cytochrome-c oxidase deficiency with repeatedly low copper and ceruloplasmin levels. These findings were suggestive of a copper metabolism disorder. In support of this, the patient's fibroblasts showed an increased copper uptake with normal retention. Detailed follow-up examinations were performed. Immunoblotting for several proteins including ATP7A (MNK or Menkes protein), ATP7B (Wilson protein) and SOD1 showed normal results, implying a copper metabolism defect other than Wilson or Menkes disease. Sequence analysis of ATOX1 and genes coding for proteins that are known to play a role in the mitochondrial copper metabolism (COI-III, SCO1, SCO2, COX11, COX17, COX19) revealed no mutations. Additional disease genes that have been associated with cytochrome-c oxidase deficiency were negative for mutations as well. As beneficial effects of copper histidinate supplementation have been reported in selected disorders of copper metabolism presenting with low serum copper and ceruloplasmin levels, we initiated a copper histidinate supplementation. Remarkable improvement of clinical symptoms was observed, with complete restoration of cytochrome-c oxidase activity in skeletal muscle.
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PMID:Congenital cataract, muscular hypotonia, developmental delay and sensorineural hearing loss associated with a defect in copper metabolism. 1590 51

Menkes disease (MD) is a neurodegenerative disorder characterized by a copper deficiency in the brain. It is caused by the defective intestinal absorption of copper resulting from a deficiency of a copper-transporting ATPase, ATP7A. This gives rise to an accumulation of copper in the intestine. The copper deficiency in the brain of MD patients cannot be improved by copper injections, because the administered copper accumulates at the blood-brain barrier and is not transported across to the neurons. To resolve this problem, we investigated the effect of a combination therapy of copper and sodium diethyldithiocarbamate (DEDTC), a lypophilic chelator, in an animal model of MD, the macular mouse. Four-week-old macular mice treated with 50 mug of CuCl2 on the 7th day after birth were used. Experimental mice were given a subcutaneous injection of CuCl2 (4 microg) and an intraperitoneal injection of DEDTC (0.2 mg/g body weight) twice a week for 4 weeks and then sacrificed. Copper concentrations and cytochrome-c oxidase activity in the brains of treated mice were higher than those of control macular mice, which received only copper or saline. The ratios of brain noradrenaline to dopamine and of adrenaline to dopamine were also increased by the treatment, suggesting that the activity of dopamine beta-hydroxylase, a copper-dependent enzyme, was improved by the treatment. Liver and renal function tests showed no abnormalities in the treated mice, although copper concentrations in the kidneys of treated mice were higher than those of control macular mice. These results suggest that DEDTC facilitates the passage of copper across the blood-brain barrier and that the combination therapy of copper and DEDTC may be an effective treatment for the neurological disturbances suffered by patients with MD.
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PMID:Effect of copper and diethyldithiocarbamate combination therapy on the macular mouse, an animal model of Menkes disease. 1643 90

Cu and Fe metabolism are known to be linked, but the interactions during pregnancy are less well studied. In the present study we used rats to examine the effect of Cu deficiency during pregnancy on Fe and Cu levels in maternal and fetal tissue and on the gene expression profile of proteins involved in Cu and Fe metabolism in the placenta. Rats were fed diets with different Cu contents before and during pregnancy. Samples were collected on day 21 of gestation. Cu levels, ceruloplasmin activity and serum Fe all decreased in maternal serum of Cu-deficient animals. Maternal liver Fe inversely correlated with liver Cu. Placental Cu levels decreased with no change in Fe. Fe and Cu levels both decreased in the fetal liver. The drop in maternal liver Cu was significantly correlated with a decrease in organ weight of fetal liver, lung and kidney. No changes were observed in mRNA expression of Cu transporter 1, Menkes P-type Cu-ATPase 7A, Wilson P-type Cu-ATPase 7B, cytochrome-c oxidase, and Cu chaperone Atox1 in the placenta of Cu-deficient dams. Transferrin receptor 1 and the Fe-responsive element (IRE)-regulated divalent metal transporter 1 (DMT1) were up regulated; while ferroportin and non-IRE1-regulated DMT1 levels did not change. These data show that Cu deficiency during pregnancy not only has a direct effect on Fe levels but also regulates the expression of Fe transporters. The pattern closely mirrors that seen in Fe deficiency, suggesting that the changes are a consequence of the decrease in serum Fe, implying that the developing fetus not only suffers from Cu, but also from Fe deficiency.
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PMID:Effect of dietary copper deficiency on iron metabolism in the pregnant rat. 1729 91